Abnormal sensitivity of skin fibroblasts from familial polyposis patients to DNA alkylating agents.
Fibroblast cell strains derived from different patients all afflicted with genetic predisposing to the development of intestinal polyposis and cancer were tested for their sensitivity to the lethal effects of the DNA alkylating agents methylmethanesulfonate (MMS), ethyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, and 4-nitroquinoline 1-oxide. The genetic syndromes studied were: (a) adenomatosis of the colon and rectum only, an autosomal dominant trait; (b) Turcot's syndrome, a rare autosomal recessive polyposis syndrome also characterized by central nervous system tumors; and (c) Gardner's syndrome, an autosomal dominant syndrome which, in addition to intestinal polyposis, is also clinically characterized by osteomas and soft tissue tumors. Survival (relative clone-forming ability) of the various polyposis fibroblast strains was compared to the average survival of three normal human fibroblast strains by t test analysis of the respective values for the inverse of the slope of the survival curve (D0) and the concentration resulting in 10% survival (D10) with p less than 0.05 considered significant. Fibroblasts from the patient with adenomatosis of the colon and rectum (strain GM2355) were moderately but significantly sensitive to 4-nitroquinoline 1-oxide with D0 and D10 values of 0.069 microM (p less than 0.05) and 0.15 microM (p = 0.01), respectively, compared with the normal values of 0.10 microM and 0.26 microM. In addition, strain GM2355 was significantly more sensitive to ethyl methanesulfonate based on D10 comparison only, 24 mM versus the normal average D10 of 28 mM (p less than 0.05). Fibroblasts from the patient with Turcot's syndrome were hypersensitive to MMS, having a D0 value of 0.24 mM (p less than 0.01) versus the normal average D0 of 0.36 mM and a D10 value of 0.95 mM (p less than 0.01) compared with the normal average value of 1.3 mM. Fibroblasts from the Gardner's syndrome proband were moderately sensitive to MMS, ethyl methanesulfonate, and N-methyl-N'-nitro-N-nitrosoguanidine due to significant differences of D10 values of 0.60 mM (p less than 0.01), 15 mM (p less than 0.01), and 4.8 microM (p less than 0.025), respectively, versus the normal average values of 1.3 mM, 28 mM, and 9.4 microM. Fibroblasts from the clinically affected Gardner's syndrome daughter of the proband were significantly more sensitive to MMS treatment, D0 of 0.22 mM (p less than 0.01) versus the normal average D0 of 0.36 mM and a D10 of 0.97 mM (p less than 0.01) versus the normal average. This differential sensitivity to the several DNA alkylating agents suggests that different mechanisms of hypersensitivity to these chemicals may be associated with fibroblasts from the various forms of familial polyposis.
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000477:Alkylating Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism* / Q000528:radiation effects; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism*; D008741:Methyl Methanesulfonate / Q000633:toxicity; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D012867:Skin / Q000187:drug effects
D000477:Alkylating Agents; D008769:Methylnitronitrosoguanidine; D015112:4-Nitroquinoline-1-oxide; D004247:DNA; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate